Reserpine-acetamide hypotensive compositions



Patented Oct. 13, 1959 RESERPlNE-ACETAIVIIDE HYPOTENSIVE COMPOSITIONSGustav J. Martin and Jay Morton Beiler, Philadelphia,

Pa, assignors to The National Drug Company, Philadelphia, Pa., acorporation of' Delaware No Drawing. Application July 20, 1954 SerialNo.- 444,643

7 Claims. (Cl. 161-67) This invention relates to and has for its objectthe provision of novel compositions (and methods for their preparation),useful as medicinals especially in the treatment of hypertension. Thecompositions of this invention comprise combinations of rauwolfia (orits more concentrated active ingredient, reserpine) with certainacetamides.

Rauwolfia is a dried extract of plants of the rauwolfia family,especially Rauwolfia serpentina. These extracts usually contain about30% by weight of the alkaloids of the plant. However, the amount ofalkaloids in the extract is not uniform and may vary from about 3% toabout 9%. The active alkaloid in the extract is reserpine and both thereserpine and the parent rauwolfia 'are known to be useful in thetreatment of hypertension.

It has now been found that the action of rauwolfia (or reserpine) ispotentia'tecl when administered in combination with certain acetamidesdescribed below. The administration may be effected by combining the twoingredients in a single dosage-unit form or by administration'of one,then the other [c.g. one may administer the rauwolfia (or reserpine)first, followed by administration of the acetamide in the desiredquantity, then by rauwolfia (or reserpine) again as desired]. The dailydosage of rauwolfia of concentration when used according to thisinvention is about 1-6 mg. (preferably about 2-4 mg.) and that of thepurified reserpine, about 100-750 gamma. The daily dosage of theacetamide used with the alkaloid is approximately 100-700 mg.

The acetamides useful in the combinations of this invention may berepresented by the general formula I GEE-CHO ON RI RH! wherein R is amember of the group consisting of hydrogen and lower alkyl; and R, R andR are each members of the group consisting of hydrogen, lower alkyl andallyl, the substituents being so chosen that R is allyl only when R" andR are not allyl. These compounds may be produced in any desired manner.One method of preparing these compounds is described in applicationSerial No. 398,428, filed December 15, 1953, and now abandoned.Particularly effective for use in the invention areallylbenzylacetamide, allyl-alpha-phenethylacetamide,N,N-diallylbenzy1acetamide and N,N-diethylallylbenzylacetamide,especially allylbenzylacetamide. Also useful in the invention are any ofthe other compounds disclosed in the above-mentioned US. applicationSerial No. 398,428.

The compositions of this invention may be prepared in any of the variousdosage-unit forms for either oral use or intravenous injection. Thus,tablets may be preparedto preferably contain about 25-250 gammareserpine (or %2 mg. rauwolfia) and about 25-250 mg. acetamide. Thismixture of active ingredients may be compounded in the usual manner tocontain fillers and/ or binders such as starch, dextrose, stearates,carbonates, kaolin or talc, then compressed to form the tablets. Alsothe mixture of active ingredients, in combination with fillers, ifdesirable, may be encapsulated for ingestion using one or two piecegelatin capsules. Furthermore, the combinations may be dissolved or'suspended for administration in liquid form; for example thecombinations may be dispensed as elixirs. Such elixirs may obviouslyinclude flavoring materials and any other desirable additives. Forintravenous injection, the combination may be dissolved in an inertsolvent or solvent mixture and administered as such. Ap'articularsolvent mixture found effective for this purpose is one containing 50%water, 25 propylene glycol and 25% ethanol.

As has been indicated above, it is possible to administer thecombinations of this invention by administering the componentsseparately, for example, by first administering the rauwolfia (orreserpine), then the acetamide or vice versa. Utilizing such procedure,the potentiating effect of the acetamide on the alkaloid is clearlyobserved. However, it is simpler to utilize the combinationsimultaneously sincev this is the most economical method.

Numerous test data have been obtained showing the in vivo effectivenessof the combinations of the invention. For example, it has been foundthat rauwolfia injected intravenously in single doses in thenormotensive dog has no appreciable blood pressure effect at unitdosages of 1.05 .0 or more mg./kg. However, when such treatment followsadministration of the acetamide, an immediately marked drop in pressureis observed. Following, in detail, are the procedures and resultsobtained by in vivo testing. The data clearly illustrate the unusualeffects obtainable as a result of applicants invention.

Dogs having normal blood pressure are injected intravenously with 0.5 or1.0 mg./kg. rauwolfia in a solution containing 25% propylene glycol, 25ethanol and 50% water. No appreciable pressure change occurs after /2hour. Then, about 200250 m-g./ kg. allylbenzylacetarnide is administeredorally to the animal. After 40 minutes, another dose of rauwolfia-isadministered. An immediate drop in blood pressure is observed lastingfrom 1 to 3 or more hours. Administration of additional dosages ofrauwolfia, either before or after pressure recovery, produce furtherdrops in blood pressure. The following are typical data obtained incarrying out the above described experiments with blood pressure valuesdesignated in millimeters of mercury.

Experiment A I II III IV Allylbenzylacetamlde, Rauwolfia, 1.0 mgJkg I.V.Ranwolfia, 0.5 mgJkg. Control Rauwolfla, 1.0 mgjkg. 50 rag/kg. orally(given 40 minutes after II) I.V. (given 1 hour I.V. (given 40 minutesafter III) after I) so 8O 1 65 80 85 85 85 85 85 85 85 85 70 65 70 70 4055 55 60 Time (mm) 0 1 10 20 40 0 10 20 30 40 0 4 10 20 10 40 60 0 1 210 20 1 This drop in pressure is transient, lasting only a few seconds.

2. The composition of claim 1 wherein the acetamide isallyl-alpha-phenethylacetamide.

3. The composition of claim 1 wherein the acetamide isN,N-diallylbenzylacetamide.

Experiment B I II III Control Allylbenzylacetaniide, Rauwolfia0.5mg./kg.I.V. Rauwolfia, 0.5 mgJkg. LV. 25 mgJkg. orally (given (given 70minutes after 11) 30 minutes after I) 100 100 70 110 100 95 95 95 9o 9595 90 so 60 85 60 45 Time (min.) o 1 3 10 2o 30 1o 20 30 40 0 1 10 63109 Tests have also been made with anesthetized dogs, 4. The compositionof claim 1 wherein. the acetamide using a combination of rauwolfia andallylbenzylacetamis N,N-diethylallylbenzylacetamide. I ide forsimultaneous oral administration. In these tests 5. The composition ofclaim 1 wherein the acetamide it has been found that administration of amixture of is allylbenzylacetamide. mg./kg. rauwolfia and 50 mg./=kg.allylbenzylacetamide 15 6. A composition of matter for the control ofhyperresults in a gradual drop in blood pressure starting aptensionwhich comprises a mixture containing reserpine proximately to minutesafter administration and and alpha-allyl-alpha-benzylacetamide inrelative proporlasting for more than 4 hours. The drop in pressure tionsof 100 to 10,000 parts by weight of said alpha allylranges from about to80 millimeters. alpha-benzylacetamide for each part of reserpine con- Inaddition the use of the rauwolfia-acetamide combina- 20 tained therein.1 tion has been found to enhance the sedative-hypnotic 7. A method ofreducing the blood pressure of animals efiects obtained when rauwolfiais administered alone. having hypertension which comprises administeringto Thus rauwolfia (5 mg./kg.) administered together with the subject anefiective amount of reserpine and a potenallylbenzylacetarnide (50rug/kg.) orally give the followtiating amount of an acetamide of thegroup consisting ing effects (administration period: 3 days): of thosehaving the formula:

(a) More prompt onset of symptoms. Marked on I second day.

(b) Greater intensity of symptoms. Depression is OHfiOHCON/ more severe.Relaxation of nictitating membrane is much more marked.

(c) Longer. recovery tune Effects last 3-4 days wherein R is a member ofthe group consisting of hydrolonger than i rauwqlfia 21101.16 gen andlower alkyl; and R, R", and R are each mem- On the basis of theillustrative data given, it is evident bers of the group consisting ofhydrogen, lower lkyl and that applicants have made a valuablecontribution to the allyl, the substituents being so chosen that isallyl medicinal art. Clearly, however, the invention may be only whenand are not auyL variously otherwise embodied within the scope of theappended claims. References Cited in the file of this patent What isclaimed FOREIGN PATENTS 1. A composition of matter in dosage unit formfor the control of hypertension containing in each dosage 5 5 Great Bmam1911 unit an amount of from about 25 to 250 gammas of reserpine and fromabout 25 to 250 milligrams of an 3681590 Great Bntam 1932 acetamide ofthe group consisting of those having the OTHER REFERENCES Remart:Annales des Chemie, vol. 8, Ser. 10 1927 R pp. 268, 272. JJHCHCON A.M.and C.T., III: 5, October 1956, p. 345.

t, Unlisted Drugs, 5:10, October 31, 1953, p. 145.

Wilkins: Use of Rauwolfia serpentina in Hypertensive Patients, New Eng.J. of Med., January 8, 1953, pp. 48- wherein R is a member of the groupconsisting of hydro- 53, esp. p. 52. gen and lower alkyl; and R, R", andR' are each mem- Rauvera (Dorsey): Modern Drugs, January 1954, p. bersof the group consisting of hydrogen, lower alkyl and 738. allyl, thesubstituents being so chosen that R is allyl Ciba, The Rauwolfia Story,63 p. booklet, Ciba y when and e n t allyl. Pharm. Prod., Inc., 1954,esp. pp. 46, 47.

Damm: Ueber die Behandlung der art. Hypertonie mit Reseipin (Serpasil),Dtsch. med. Wschr., vol. 79, January 1, 1954, pp. 39-41 (trans, 7 pp.plus 2 pp. tables).

1. A COMPOSITION OF MATTER IN DOSAGE UNIT FORM FOR THE CONTROL OFHYPERTENSION CONTAINING IN EACH DOSAGE UNIT AN AMOUNT OF FROM ABOUT 25TO 250 GAMMAS OF RESERPINE AND FROM ABOUT 25 TO 250 MILLIGRAMS OF ANACETAMIDE OF THE GROUP CONSISTING OF THOSE HAVING THE FORMULA: